Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

Hum Mutat. 2022 Jul;43(7):832-858. doi: 10.1002/humu.24371. Epub 2022 Apr 14.


Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

Keywords: CNGA3; achromatopsia; cyclic nucleotide-gated ion channel; in silico analysis; variant classification; variant spectrum.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Color Vision Defects* / genetics
  • Cyclic Nucleotide-Gated Cation Channels* / genetics
  • Humans
  • Mutation
  • Retinal Cone Photoreceptor Cells


  • CNGA3 protein, human
  • Cyclic Nucleotide-Gated Cation Channels

Supplementary concepts

  • Achromatopsia 3